Presynaptic inhibition of gamma-aminobutyric acidB-mediated synaptic current by adenosine recorded in vitro in midbrain dopamine neurons

YN Wu, NB Mercuri and SW Johnson

Department of Pharmacology, Oregon Health Sciences University, Portland, USA.

Adenosine receptor antagonists such as caffeine cause dopamine- dependent behavioral arousal and hyperlocomotion in rodents. In the present study, we used the whole-cell recording technique in the rat brain slice to investigate effects of adenosine on dopamine neurons and their synaptic inputs in the substantia nigra zona compacta and ventral tegmental area. Adenosine was most potent for inhibiting the amplitude of the inhibitory postsynaptic current (IPSC) mediated by gamma- aminobutyric acid (GABA)B receptors (EC50 = 47 +/- 3 microM) compared with inhibition of the GABAA-mediated IPSC (117 +/- 51 microM) and the excitatory amino acid-mediated excitatory postsynaptic current (119 +/- 36 microM). Adenosine failed to inhibit current evoked by exogenous GABA or baclofen, suggesting that adenosine acted presynaptically to reduce GABA release from nerve terminals. Adenosine inhibited the GABAB- mediated IPSC by acting at the adenosine A1 receptor, because its effect was blocked by the selective adenosine A1 receptor antagonist 8- cyclopentyl-1,3-dipropylxanthine (100 nM), as well as by the methylxanthines caffeine (1 mM) and theophylline (300 microM). The rank- order of potency of adenosine agonists [N6-cyclohexyladenosine > R-(-)- N6-(2-phenylisopropyl)-adenosine = N6- cyclohexyladenosine > 5'-N- ethylcarboxamidoadenosine > 2-chloroadenosine] also was consistent with activation of the adenosine A1 receptor, whereas the selective adenosine A2A agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5'- N-ethylcarboxamido adenosine] had no effect on the GABAB IPSC. None of the adenosine agonists or antagonists affected holding current or membrane conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 273, Issue 2, pp. 576-581, 05/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

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